Abstract Systems vaccinology approaches are defining molecular signatures that can predict vaccine induced immune responses in humans. These studies have mostly used healthy adults and two important vaccine target populations, children and the elderly, have not been examined in detail. In this proposal we extend the systems vaccinology approach to these two target populations at the extremes of age; infants (12-15 months old) and the elderly over 70 years. Herpes zoster (shingles), which is caused by VZV, affects several million people/year globally and is a significant public health concern for the elderly. Zostavax, the currently licensed live VZV vaccine against zoster, has limited efficacy in subjects >70yrs old. An investigational recombinant glycoprotein E subunit vaccine (gE vaccine) has shown promising results in phase I trials but no comparative studies have been done with these two vaccines. In Aim 1 we will characterize the adaptive immune response induced by the live Zostavax versus gE vaccine in the elderly. These studies will provide insight into which zoster vaccine induces more effective and durable immunity. VZV also causes chickenpox in children and the live Varivax vaccine is highly effective in preventing chickenpox yet there is a paucity of knowledge about the nature of innate and adaptive immunity to vaccination in the pediatric population. In Aim 2 we will conduct a detailed analysis of the T and B cell responses induced by Varivax in infants and children. These studies in Aims 1 and 2 should provide new insights into understanding the immune response to the same vaccine at the two extremes of age. Finally, in Aim 3, we will use systems vaccinology approaches to probe the immune response of transplant recipients to vaccination against pneumococcal diseases. Our proposed studies with this immunocompromised population that is at high risk against invasive pneumococcal disease could provide new guidelines for pneumococcal vaccination in transplant recipients. To address these fundamental questions about vaccine-induced responses in these human populations we have assembled a team of investigators for Project 2 with highly complementary expertise in immunological memory (Ahmed), B cell molecular biology (Wilson) and VZV T cell immunity (Weinberg).